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Mirtazapine toxicity in cats in retrospect

Ferguson, L. E., McLean, M. K., Bates, J. A., & Quimby, J. M. (2016). Mirtazapine toxicity in cats: retrospective study of 84 cases (2006-2011). J Feline Med Surg, 18(11), 868–874.

The use of mirtazapine as an appetite stimulant in cats has been discussed previously on this blog, but remains an important topic due to its widespread use in feline medicine. As previously mentioned, appetite stimulants allows for the nutritional support of feline patients until they are able to recover from a disease or as a part of palliative care. While feeding tubes or parenteral nutrition are sometimes required in ill cats, appetite stimulants are generally less expensive, well tolerated and easily administered. While other appetite stimulants (such as cyproheptadine) are available, mirtazapine is generally the first line choice of most clinicians due to its efficacy and minimal side effects.

Mirtazapine acts through a variety of mechanisms at alpha-2, serotonin, and norepinephrine receptors. Its primary mode of action as an anti-emetic and appetite stimulant is likely through antagonism of 5-HT3 receptors. These effects lead to increased appetite within hours of drug administration that are repeatable through multiple dose and last in the range of 24 hours. As with any drug, cats administered mirtazapine may experience negative effects. There adverse effects, when they occur, are primarily serotonergic in nature. Mild signs of toxicity include agitation, nausea, low-grade fever, and tachycardia. Less common but more severe signs include life threatening hyperthermia and rigidity.

The purpose of this manuscript was to determine the most common adverse effects associated with mirtazapine administration and the doses associated with these effects. The study was designed as a retrospective observational study utilizing the ASPCA Animal Poison Control Center’s electronic medical record database.

A total of 84 cats were enrolled in the study with data available on signalment, intended use and dose of mirtazapine, route, onset time, clinical signs and duration of illness, and final outcome. Similar signs were grouped together and data were analyzed based on dose, type of signs, and number of cats affected. The majority of adverse effects occurred with doses of 15mg/cat and by 3.75mg/cat, followed by 7.5mg and then all other doses. These are not unexpected as they represent the accidental administration of a full 15mg tablet (either due to owner or prescribing errors) or intended use at 3.75mg.  More clinical signs were seen with higher doses.

Clinical signs began between 15minutes and 3 hours and lasted between 1 and 48 hours. Treatments were varied and included IV or SQ fluids, reversal with cyproheptadine (which antagonizes the effects of mirtazapine), decontamination with emesis or charcoal, sedatives, and others.

Historically, mirtazapine has been prescribed at a variety of doses, including a common dose of 3.75mg every 3 days. This dose lacks pharmacologic backing, and significant published data indicates that a lower dose of 1.88mg every 24 hours (every 48 hours in cats with chronic kidney disease) is equally effective at appetite stimulation.  This paper further demonstrates that a dose of 3.75mg is associated with significantly more adverse effects. Lack of increased efficacy and increased risk of toxicity would indicate that a 3.75mg dose should be discarded in favour of a 1.88mg dose.

There are some limitations with this study. Its retrospective nature means that many cats did not have full information available, and in many cases multiple doses of mirtazapine may have been administered. Underlying disease states may also have contributed and were not controlled for. Full data on treatments and response were also not available.

The conclusions drawn by this paper suggest that mirtazapine toxicity is a reasonable concern in veterinary medicine. While the adverse effects of mirtazapine are generally not life threatening, the potential for serious complications such as serotonin syndrome do exist. Even mild symptoms such as panting, nausea and dysphoria may cause significant stress to owners and quality of life issues to cats, especially medically unstable cats who require appetite stimulants. While many cases of toxicity were due to accidental overdose, several were seen at the prescribed dose.

Two basic steps may be taken to avoid mirtazapine toxicity. The first is to utilize an appropriate dose of 1.8-2.0mg/cat administered every 24 hours (less often for cats with kidney disease). The second is to use compounded drug at the intended dose, rather than relying on owners to correctly fraction the commercial 15mg tablets. These steps should dramatically reduce the incidence of adverse effects from this beneficial drug. (MRK)

See also:
Agnew W, Korman R. Pharmacological appetite stimulation: rational choices in the inappetent cat. J Feline Med Surg 2014; 16: 749–756.